Collagen and elastin are mainly distributed throughout skin, bones, cartilages, joints, and blood vessels. Furthermore, collagen and elastin are also broadly distributed throughout teeth, tendons, digestive tracts, lungs, uteri, and the like. Abnormalities in collagen or elastin metabolism are known to cause various disorders in all organs in which they are distributed. In particular, 40% of collagen is present in the skin and 20% is present in bones and cartilages. Collagen is also broadly distributed in blood vessels and visceral organs. As represented by a congenital disease, Ehlers-Danlos syndrome, it is well known that abnormalities in enzymes essential for collagen synthesis induce the development of symptoms including overelasticity and friability of the skin, hypermobility and dislocation of joints, fragility of the blood vessels and bleeding, or the like. Moreover, complications may be developed, for example, in cardiovascular system (e.g., heart valve disease, aortic dissection, and vascular bulge (aneurysm or varicose vein)), in osteocartilaginous system (e.g., osteoarthritis, deformity of spine, and hernia), in visceral system (e.g., bowel rupture, uterine rupture, bladder rupture, pneumothorax, and emphysema), in ophthalmic system (e.g., rupture of eyeballs and retinal detachment), and in dental system (e.g., loss of teeth and dental periostitis). An example of such a complication known for many years is scurvy, wherein abnormalities in collagen synthesis are caused by vitamin C deficiency. Scurvy causes fragile blood vessels, resulting in subcutaneous bleeding, gingival bleeding, or visceral bleeding as well as systemic symptoms such as fragile bones or skin.
Studies in recent years have revealed that collagen is required as a foothold upon bone or cartilage formation, thereby confirming the pathological conditions of osteocartilaginous symptoms due to abnormalities in collagen metabolism. Actually, clinical test results reported that the symptoms of osteoarthritis or chronic rheumatism are ameliorated by the administration of collagen or a collagen peptide. Furthermore, it has also been reported that in an animal experiment, osteoporosis was ameliorated by the administration of a collagen peptide. Collagen is also an essential factor in the healing of wounds. When collagen degradation levels are greater than collagen synthesis levels, the healing process does not work, and it may lead to ulceration.
Furthermore, collagen and elastin are distributed throughout the skin and are particularly distributed in dermis. They are thought to be essential for maintaining flexibility and elasticity of the skin, respectively. Abnormalities in collagen and elastin metabolism wherein degradation levels are higher than synthesis levels and total amounts of collagen and elastin decrease result in so-called skin-aging symptoms, such as wrinkles, sagging skin, and flecks. Skin-aging symptoms are increased by ultraviolet irradiation such as sunburn. However, it has been revealed in recent years that the pathogenesis thereof is also associated with abnormalities in collagen and elastin metabolism.
Furthermore, collagen and elastin are important in maintaining the strength and elasticity of the walls of blood vessels. In the cases of congenital diseases (e.g., Ehlers-Danlos syndrome) that are caused by abnormalities in the genes of enzymes required for the synthesis of collagen and elastin, it is known that aneurysm formation, the dissection of arteries, and arterial rupture occur. Similarly, it has been reported that aneurysm formation, the dissection of arteries, and arterial rupture are also developed in lysyl oxidase (LOX) gene-deficient mice (lacking LOX, which is an enzyme required for the synthesis of both collagen and elastin) and also in type I or type III collagen gene-altered mice. Moreover, it is thought that the onset of acute coronary syndrome (acute myocardial infarction, unstable angina, and sudden death) is due to the rupture of coronary atherosclerotic plaque. Enhanced collagen and elastin degradation and the resulting thinning and weakening of fibrous capsules are involved in the pathogenesis of unstable and easy-to-rupture plaques.
Various primary causes of aneurysms are known, such as arteriosclerosis, inflammation, infection, and congenital anomaly. All of these cases are characterized by dilatation of the aorta or the peripheral arteries. Specifically, such dilatation is due to weakening of aortic walls that is directly caused by abnormalities in collagen and elastin metabolism. As aneurysms, true aneurysms that involve dilation of all layers of the walls, and dissecting aneurysms that occur when blood flow forces the layers of the wall of the aorta apart are known. Both aneurysms are disorders that involve enlarged aneurysm diameter as the disorders progress and eventual rupture leading to death if untreated. Although aneurysms are clinically important disorders, currently the best available therapeutic method that can be employed for improving the prognosis is surgical therapy (e.g., surgical repair or stentgraft deployment) alone. However, surgery itself is severely burdensome for patients and surgical risk is often higher than the risk of aneurysmal rupture. Hence, a new low-invasive therapy for aneurysms, and particularly pharmacotherapy for the same, have been desired.
As described above, it is thought that aneurysms occur when the aortic wall is weakened due to enhanced degradation or abnormalities in the synthesis of the extracellular matrix, in particular, collagen and elastin that composes the aortic wall. Aneurysms then progress and result in rupture thereof. Actually, enhancement of various factors involving extracellular matrix degradation in human aortic aneurysms has been observed. In particular, matrix metalloproteases (MMPs) composing a group of extracellular-matrix-degrading enzymes, and are thought to be essential for the development and the progression of aneurysms and have been a focus of attention. Because the development of experimental aneurysms is prevented in mice lacking the genes of MMPs. Moreover, there is a report demonstrating prophylaxis with respect to the development of experimental aneurysms in model animals using a drug possessing MMP inhibitory activity. However, in the U.S. and Europe, clinical trials concerning MMP activity inhibitory agents have been conducted for preventing enlargement of aneurysm diameter in small-sized abdominal aortic aneurysms. Nevertheless, no significant effects of preventing the progress of aneurysms have been reported to date (J. Vascular Surgery 36: 1-12 (2002)).